Fish gelatin compositions containing a hydrocolloid setting system

ABSTRACT

The invention concerns Gelatin compositions for the use in pharmaceutical, veterinary, food, cosmetic or other products like films for wrapping food, aspics or jellies, preferably for predosed formulations like soft or hard gelatin capsules wherein the gelatin used is of non-bovine and non-pig origin and preferably derived from fish, poultry or plant sources. Especially preferred are film compositions for hard gelatine capsules prepared from fish gelatin.

RELATED APPLICATIONS

This application is a continuation of and claims the benefit of priorityunder 35 U.S.C. § 120 to U.S. Ser. No. 09/804,093 filed Mar. 12, 2001now U.S. Pat. No. 6,770,294 which is a continuation of U.S. Ser. No.09/220,933 filed Dec. 24, 1998 now abandoned which claims the benefitpursuant to 35 U.S.C. § 119(a)–(d) of prior application filed Dec. 26,1997 in France as application number 9716574 and PCT/US98/23474, filedNov. 4, 1998.

FIELD OF THE INVENTION

The invention concerns gelatin compositions for the use inpharmaceutical, veterinary, food, cosmetic or other products like filmsfor wrapping food, aspics or jellies, preferably for predosedformulations like soft or hard gelatin capsules wherein the gelatin usedis of non-bovine and non-pig origin and preferably derived from fish,poultry or plant sources. Especially preferred are film compositions forhard gelatine capsules prepared from fish gelatin.

A second embodiment of the invention is the use of the film compositionfor the manufacturing of hard gelatin capsules by conventional dipmoulding processes.

The gelatin used for hard gelatin capsules is traditionally produced byextraction from collagen containing mammalian tissues, particularly suchas pig skin and bovine bone. Gelatin from pig and bovine origin arepreferably used for their gelling, film forming and surface-activeproperties. The manufacture of hard gelatin capsules by dip mouldingprocess exploits fully its gelling and film forming abilities. Suchcapsules are manufactured by dipping mould pins into a hot solution ofgelatin, removing the pins from the gelatin solution, allowing thegelatin solution attached on pins to set by cooling, drying andstripping the so-formed shells from the pins. The setting of thesolution on the mould pins after dipping is the critical step to obtainan uniform thickness of the capsule shell.

Fish collagen is a further source of gelatin. However, it has long beenknown that gelatin derived from fish collagen lacks much of the gellingand setting ability of mammalian gelatins which limits the fish gelatinapplication. It is only applicable for products where a high viscosityof the solution without gel formation is desired, for example, in glueor food manufacturing. In the field of predosed pharmaceuticals, thefish gelatin can be used for micro-encapsulation (WO 9620612) or for theproduction of soft capsules where the gelling and setting ability is nota critical parameter in the manufacturing process.

BACKGROUND OF THE INVENTION

A. N. Fraga et al. describe in J. Polym. Mater. 5 (1988) 49–55 themechanical properties from fish Gelatins as a brittle behaviorcharacteristic of a glassy material at normal temperatures. Such abrittleness is very undesired property for a gelatin capsule.

Norland Products Inc. describe in Research Disclosure 1987, 788 thatwater solutions of fish gelatin remain liquid down to 10° C., wheraswater solutions of animal gelatin must be heated to temperatures over30° C. to remain liquid. This behavior of fish gelatin will not allowthe use in the conventional dip moulding process at conventionaltemperatures because of ist to low gelling temperature.

B. Leuenberger describes in Food Hydrocolloids 1991, 353-361 viscosityand gelation properties of different mammalian and fish gelatins withthe conclusion that fish gelatin may be usefull in applications wherehigh solution viscosity without gel formation is desired.

Surprisingly it has been found that fish gelatin can be used for theproduction of conventional Gelatins with conventional properties byadding a setting system to the aqueous fish gelatin solution.

SUMMARY OF THE INVENTION

The problem of the invention is therefore the provision of compositionsfor the production of Gelatins for the use in pharmaceutical,veterinary, food, cosmetic or other products like films for wrappingfood, aspics or jellies, preferably for predosed formulations like softor hard gelatin capsules wherein the gelatin used is of non-bovine andnon-pig origin and preferably derived from fish, poultry or plantsources, and wherein a setting system is added to the aqueous gelatinsolution. Especially preferred are film compositions for hard gelatinecapsules prepared from fish gelatin.

Surprisingly this is achieved by the addition of a setting system andthis allows the use of a wide range of gelatins from other sources thanpigs or cattle for gelatin products for human consumption avoidingethical and cultural problems.

BRIEF DESCRIPTION OF THE DRAWING

The sole Figure is a graph showing the percentage of acetaminophendissolved from capsules produced in accordance with the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The addition of a setting system to the aqueous gelatin solution enablesthe adaption of specific and desired gelling properties also to gelatinsolutions with normally insufficient gelling behavior, especially forthe production of hard gelatin capsules. For the production of suchcapsules it is extremly important that the film forming gelationsolution remaining on the mould pins after dipping is prohibited fromflowing down the pins. Otherwise the obtained film will not have thedesired uniform thickness.

Consequently hard gelatin capsules from other gelatin sources can beproduced with the same equipment as for conventional hard gelatincapsules in the range of same process conditions. Furthermore capsulesproduced from compositions of the instant invention have the samedimensional specifications and allow the use of the existing fillingmachinery and do not require specific and new equipment for the capsuleusers. The capsules produced from the gelatin compositions of theinvention have also acceptable mechanical and dissolution properties.

The gelatin concentration in the dipping solution is in a range of 10 to60%, preferably in the range of 20 to 40% by weight.

The setting system consist of a hydrocolloid or mixtures ofhydrocolloids and cations and may contain in addition sequesteringagents.

Suitable hydrocolloides or mixtures producing synergistic properties maybe selected from natural seaweeds, natural seed gums, natural plantexudates, natural fruit extracts, bio-synthetic gums, bio-syntheticprocessed starch or cellulosic materials, preferred are thepolysaccharides.

The preferred polysaccharides are alginates, agar gum, guar gum, locustbean gum (carob), carrageenan, tara gum, gum arabic, ghatti gum, Khayagrandifolia gum, tragacanth gum, karaya gum, pectin, arabian (araban),xanthan, gellan, starch, Konjac mannan, galactomannan, funoran, andother exocellular polysaccharides. Preferred are exocellularpolysaccharides.

The preferred exocellular polysaccharides are xanthan, acetan, gellan,welan, rhamsan, furcelleran, succinoglycan, scleroglycan, schizophyllan,tamarind gum, curdlan, pullulan, dextran. Preferred arekappa-carrageenan or gellan gum or combinations like xanthan with locustbean gum or xanthan with konjac mannan. The amount of the hydrocolloidis preferably in the range of 0.01 to 5% by weight and especiallypreferred 0.03 to 1.0% in the aqueous gelatin solution.

The cations are preferably selected from, K⁺, Na⁺, Li⁺, NH₄ ⁺, Ca⁺⁺ orMg⁺⁺, for kappa-carrageenan are preferred K⁺, NH₄ ⁺ or Ca⁺⁺.

The preferred sequestering agents are ethylenediaminetetraacetic acid,acetic acid, boric acid, citric acid, edetic acid, gluconic acid, lacticacid, phosphoric acid, tartaric acid or salts thereof, methaphosphates,dihydroxyethylglycine, lecithin or beta cyclodextrin and combinationsthereof. Especially preferred is ethylenediaminetetraacetic acid orsalts thereof or citric acid or salts thereof. The amount is preferably0.01 to 3%, especially 0.1 to 2% by weight of the dipping solution.

Among the setting systems mentioned above, the systems ofkappa-carrageenan with cation and gellan gum with cation arespecifically preferred. They produce high gel strength at lowconcentrations and have excellent compatibility with gelatin.

The Gelatins produced from the dipping solutions as described willconsequently by a water content of 7 to 17% by weight contain by weight83 to 93% gelatin, 0.01 to 10%, preferably 0.1 to 3% hydrocolloids,0.001 to 3%, preferably 0.01 to 1% cations depending on thehydrocolloids used, and optional 0.001 to 3%, preferably 0.01 to 1%sequestering agents.

Capsules or films with the inventive gelatin composition may bemanufactured with conventional machines by the conventional processeslike extrusion moulding, injection moulding, casting or dip moulding.

The inventive gelatin composition may contain additionally acceptableplasticizers in an range from about 0 to 40% based upon the weight ofthe gelatin. Suitable plasticizers are polyethylene glycol, glycerol,sorbitol, sucrose, corn syryp, fructose, dioctyl-sodium sulfosuccinate,triethyl citrate, tributyl citrate, 1,2-propylenglycol, mono-, di- ortriacetates of glycerol, natural gums or the like as well as mixturesthereof.

The inventive gelatin composition may contain in a further aspectadditionally pharmaceutically or food acceptable coloring agents in therange of from 0 to 10% based upon the weight of the gelatin. Thecoloring agents may be selected from azo-, quinophthalone-,triphenylmethane-, xanthene- or indigoid dyes, iron oxides orhydroxides, titanium dioxide or natural dyes or mixtures thereof.Examples are patent blue V, acid brilliant green BS, red 2G, azorubine,ponceau 4R, amaranth, D+C red 33, D+C red 22, D+C red 26, D+C red 28,D+C yellow 10, yellow 2 G, FD+C yellow 5, FD+C yellow 6, FD+C red 3,FD+C red 40, FD+C blue 1, FD+C blue 2, FD+C green 3, brilliant black BN,carbon black, iron oxide black, iron oxide red, iron oxide yellow,titanium dioxide, riboflavin, carotenes, anthocyanines, turmeric,cochineal extract, clorophyllin, canthaxanthin, caramel, or betanin.

The shaped gelatin composition of the invention or the final producttherof may be coated with a suitable coating agent like celluloseacetate phthalate, polyvinyl acetate phthalate, methacrylic acidgelatins, hypromellose phthalate, hydroxypropylmethyl cellulosephthalate, hydroxyalkyl methyl cellulose phthalates or mixtures thereofto provide e.g. enteric properties.

The gelatin composition of the invention may be used for the productionof containers for providing unit dosage forms for example foragrochemicals, seeds, herbs, foodstuffs, dyestuffs, pharmaceuticals,flavoring agents and the like.

The inventive gelatin composition makes it useful for the encapsulationof caplets in a capsule, especially in a tamper-proof form. Theencapsulation of a caplet in a capsule is preferred processed by coldshrinking together capsule parts, which are filled with a caplet, whichcomprises the steps providing empty capsule parts, filling at least oneof said capsule parts with one or more caplets, putting said capsuleparts together, and treating the combined capsule parts by coldshrinking.

The inventive gelatin composition is also useful for encapsulating andsealing the two capsule halves in a process in which one or more layersof the composition are applied over the seam of the cap and body, or bya liquid fusion process wherein the filled capsules are wetted with ahydroalcoholic solution that penetrates into the space where the capoverlaps the body, and then dried.

A specific embodiement of the instant invention is a hard gelatincapsule from fish gelatin filled with fish oil.

The improved properties of the gelatin composition are demonstrated bythe following examples:

EXAMPLE 1

To 3.39 kg of deionised water is added 5 g of potassium acetate (0.10%by weight in the solution), followed by addition of 10 gkappa-carrageenan (0.20% by weight) under stirring at about 70° C. Whena clear solution is obtained 1.60 kg of fish gelatin (32% by weight) areadded at 60° C. under slow stirring until the gelatin is completelydissolved and the solution is defoamed.

The fish gelatin solution thus prepared is then poured into a dippingdish of a pilot machine of conventional hard gelatin capsule productionequipment. While keeping the temperature of dipping fish gelatinsolution at about 50° C., natural transparent hard fish gelatin capsulesof size 1 were produced according to the conventional process with thesame dimensional specifications to the conventional hard gelatincapsules.

EXAMPLE 2

To 5 kg of fish gelatin solution at 60° C., prepared according toexample 1, are added 32.6 g of titanium dioxide previously dispersedinto a small quantity of water. After homogenising the solution, it ispoured into the dipping dish, and white opaque hard fish gelatincapsules of size 1 were produced as in the example 1.

The capsules from both examples have excellent dissolution properties asdemonstrated in FIG. 1, showing the percentage of acetaminophendissolved from capsules immersed in deionised water at 37° C. (USPXXIII) as a function of dissolution time.

1. A gelatin composition comprising 83 to 93% by weight of fish gelatin,7 to 17% by weight of water and 0.01 to 10% by weight of a hydrocolloidsetting system containing at least one of the following, naturalseaweeds, natural seed gums, natural plant exudates, natural fruitextracts, bio-synthetic gums, bio-synthetic processed starch, cellulosicmaterials and polysaccharides, said hydrocolloid setting systemadditionally containing cations and a sequestering agent, saidhydrocolloid setting system providing the gelatin composition withgelling properties similar to non-fish gelatin containing gelatincompositions so that the gelatin compositions may be used to make hardgelatin capsules.
 2. The gelatin composition according to claim 1wherein the hydrocolloid setting system contains polysaccharides.
 3. Acontainer for housing a unit dosage form of an active agent comprisingthe gelatin composition of claim
 1. 4. The container according to claim3 wherein the active agent is selected from the group consisting ofagrochemicals, seeds, herbs, foodstuffs, dyestuffs, pharmaceuticals, andflavoring agents.
 5. The container according to claim 4, wherein theactive agent is a pharmaceutical agent.
 6. The container according toclaim 3 further comprising a coating.